A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma

@Jonathan Edwards I’m jumping the gun a bit but does the mechanism you propose predict that ME/CFS is a neuro-immune disease? If not, what would be an accurate description?

 

I have approx 3 days PEM, or rather 2 days, as the first day after the activity I feel OK. It starts on the second day after activity.

 

What is a neuro-immune disease, Robert?
I don't think of RA as an arthro-immune disease.

An accurate description of the disease process is likely to require about six pages.

If you call it a neuro-immune disease you will get all these twitterati immuno-twits lumping it in with lots of other diseases and talking immunobabble.

 

love the neologisms

 

Doesn't the classification matter when it comes to things such as being eligible for vaccines (and maybe other stuff I don't know about)? IIRC, Covid vaccines were prioritised for people with neurological conditions, among others.

Also, our charities are going to have to call it something!

Do you think the categories are meaningful at all? If you don't think of RA as an arthro-immune disease, what do you think of it as?

 

From what I read it seems reasonable to expect upregulation of FcGRI if those receptors are stimulated in at least some cell types. For example in Neutrophils researchers have found FcGRI has a fold change increase in expression in some bacterial infections and in the lab upon stimulation (4x-10x).

@Jonathan Edwards Have you been able to ask researchers who have single cell sequencing data if they have seen an increase in expression of FcGRI in any particular cell types? While absence of an increase does not rule out this theory it would be nice if there was supporting data.

Another question, how quickly can FcGRI numbers increase and decrease? I got the impression it can be quite quick. That would make sense in neutrophils as they seem to have a lifespan of hours to a few days.

 

My first thought was that this could explain why I don’t know my antigen from my elbow…

But maybe a nerve needs to know about localised things for other reasons. Perhaps its just a hangover that lots of cells have from earlier cell evolution. Or could it be that it’s useful for a nerve to know certain things are around in the extra cellular fluids so it stops sucking up stuff up? Or should it get those messages from elsewhere, other immune cells?

 

Neuro-immune is not a recognised classification and anyway, when it comes to policy each condition gets treated on its own merits. Carpal tunnel syndrome is a neurological condition but does not justify vaccination priority!

They can call it ME/CFS. RA charities have never had to put RA in a special classification.

Various categories can be useful at times but not 'Neuro-immune' or whatever.


An interesting point is that 'autoimmune' is useful at times but only if it is used sensibly and conditions like psoriasis are separated off as 'auto-inflammatory'. If ME/CFS has the sort of mechanism I am suggesting, it is going to be neither of those, because it is not inflammatory. But there is only really any need for such a grouping if there is another condition to put ME/CFS with in a group. That might be what people tend to call fibromyalgia but I would wait until we know a bit more

 

I would expect FcRI to be increased on macrophages that have taken up residence in particular tissue microenvironment with T cells. I would not expect it to occur in the circulation. We don't have any data on macrophages in environments with T cells. I also think that my model does not necessarily predict you would see anything unusual because of the complexity of the cellular architecture in places like lymph node.

Upregulation of FcRI would, at a guess, take an hour or two. Basically time to make some new protein from RNA.

 

That seems unlikely because it looks to be specific nerves expressing it and proteins with highly specific functions like this don't usually hang around where they are not wanted. I am puzzled but there is likely to be a neat explanation. Somebody may have thought of one but the discussion sections of the papers I have seen are a bit pedestrian.

 

If you can afford this is a rather enlightening course: https://pll.harvard.edu/course/hmx-immunology

For much cheaper this book goes into even further detail:
https://www.thriftbooks.com/w/the-i...oaAjqNEALw_wcB#idiq=33190566&edition=13718438

 

If you had a transcriptional change in a DRG cell for instance, as a result of some (immune) signalling in the DRG itself, how long would it take to move mRNA along microtubules in the axon to be presumably translated in the nerve endings in the tissues. A PEM delay type length of time?

 

I would need to ask a friend.
Lots of others here would give a better guess.

I am not sure that there are ribosomes at the afferent end of the forked axon. Maybe protein is transported. Microtubules can transport even mitochondria quite quickly I think but not sure how quick.

Edit: Google says all these things can happen...

 

Ah I see! Either way any transcriptional change in the neuron must take a while to affect the protein composition at its terminals. @Snow Leopard or others do you know how long a change in neuron excitability might take to appear after a signaling event? Could it be done almost instantly by slightly changing the polarity near the cell body - or does it require a change in levels of eg ion channels at the nerve endings themselves?

 

I don’t know – that’s why I asked the question.

As a layman, I would describe RA as an autoimmune disease, and FMF as a hereditary auto-inflammatory disease (or disorder).

If your hypothesis was correct, what would be the most accurate equivalent answer to the question: What is ME/CFS?

Would it fit the definition of a disease or would it still be more accurately described as a syndrome or something else in your view?

 

I don't know. Auto-inflammatory is a bit of a con really because it isn't really auto. It is more spontaneous inflammatory maybe. Robin Coombs always pointed out that even autoimmunity is wrong because you are not immune to self. If anything it is auto-sensitivity.

I think we are beginning to see that ME/CFS really is a disease, or maybe two. I think there is an important question about whether it is one or two diseases - or at least whether the same combination of immune and neural processes is more or less universal or whether they are more modular.

 

Will each PwME be able to have a guess at which of the two they have, based on symptoms? Will they have different treatments? And prognoses?

 

I may not be 100% correct about this in the specific neuronal context, but in most cells the translation happens either within the ER or in nearby free-floating ribosomes in the cytosol and would be in close proximity to the nucleus either way. It’s typically folded proteins that traffic along microtubules via chaperone motor proteins, or they just might diffuse in the cytosol if they don’t need to be moved particularly far. Rate would be around the order of a couple micrometers per second, if my memory serves for microtubule transport. I have no idea if this can simply be scaled up linearly to the length of a typical neuron, though.

[Edit: https://elifesciences.org/articles/81721 may be an interesting read @chillier though not sure how generalizable it is]

 

My understanding was, that could be misremembered, that in neurons you can get mRNA packaged up into riboproteins that can be shuttled along microtubules to the ends of the neurons. In this way you would have a little bit of an ability to quickly respond to signals locally with regulation at the translation level. Maybe this happens in some situations and not others.

2um/s sounds pretty nippy to me. Assuming that's right then it would take 42 hours to move something 30cm along microtubules - possibly the right kind of time scale.

 

I am not sure that we have good reason to think that the neuron needs to express anything more down at the sensory receptor end. Shifting calcium balance around the cell soma might make more sense - in response to signals from receptor there. These neurons are odd in that they tend to have a single forked axon that functions both as afferent and effect from the cell body. The cell body might seem just to be a source of structural proteins but it might control propagation from one axon fork to the other by modulating calcium at that point?